Many polymeric materials, including hyaluronic acid, derivatized forms thereof, and its conjugates, can be used as injectable biomaterials, as well as in medical devices and implantable materials. Typically, use as an injectable material, medical device, implantable material or the like requires sterilization prior to storage or use. Unfortunately, many polymeric materials are fragile to common sterilization procedures. Sterilization can often lead to pronounced changes in the physico-chemical properties of the polymer post-sterilization, such that the resulting sterile polymer composition is rendered unsuitable for its intended use.
Sterilization methods that are currently applied to medical materials include, for example, heat treatment, high-pressure vapor sterilization (e.g. autoclave sterilization), ethylene oxide gas (EOG) sterilization, supercritical carbon dioxide sterilization and radiation sterilization. See for example, U.S. Pat. No. 6,891,035, U.S. Pat. No. 6,149,864, U.S. Pat. No. 5,621,093, U.S. Pat. No. 4,263,253, and U.S. Patent Publication Nos. US 2006/0292030, and US 2007/0009578. Available sterilization methods are typically assessed in relation to the robustness of the particular composition to be sterilized. For example, high-pressure vapor sterilization may be used for a medical material only to the extent that the material can endure high temperatures and high pressures. However, few biocompatible compositions can endure high temperatures and high pressures. EOG sterilization is useful because the process suppresses the deterioration of the material. However, residual ethylene oxide has an adverse effect on living organisms, such as hemolysis and other toxic reactions.
Many biomaterials have been reported to suffer deleterious effects upon sterilization. For example, chitosan solutions show a dramatic decrease in viscosity after 25-kGy gamma sterilization (Zahraoui, C., Sharrock, P., Bone, 25 (2), Supp. 1, August 1999, p. 63S-65S). Heat sterilization has also been described to degrade chitosan solutions, while ultrafiltration is difficult due to the high viscosity of the material (Zahraoui, ibid). Aqueous co-polylactide solutions show, by capillary electrophoresis, that hydrolysis occurs to liberate monomers following 25-kGy gamma sterilization (Zahraoui, ibid). Additionally, gel exclusion chromatography of gelatin reveals crosslinking of the chains due to irradiation (Zahraoui, ibid). Further, monomers used in standard acrylic cements are typically sterilized by ultrafiltration because they are unstable upon irradiation.
Based upon the foregoing, it can be seen that sterilization of polymer-based materials is not at all routine, and provides numerous challenges to arrive at a substantially intact sterile product, particularly in the case of a reactive polymer.